Introduction
A major contributor to hereditary blindness is a set of heterogeneous inherited retinal degenerations known as retinitis pigmentosa (RP). Due to the loss of rod photoreceptors, the condition is initially characterized by night blindness and an early loss of the peripheral vision field. Cone photoreceptor degradation, which happens as the illness worsens, is the cause of late central vision loss. Patients have severe functional vision loss and blindness at this late stage.
Cone photoreceptor loss has been demonstrated to follow the death of rod photoreceptors and is most likely brought on by oxidative stress or the absence of nearby trophic effects like glucose transport. While cones are specially made for exact center acuity and color vision, rods are responsible for seeing in low light and peripheral vision. Recent research has demonstrated that cone starvation and loss eventually occur from the loss of rod photoreceptor outer segment contact with the Retinal pigment epithelium (RPE). The illness develops gradually, and the loss of photoreceptors is continual and progressive. Since patients frequently receive a diagnosis of the disease only when it has progressed to an advanced stage, it has been demonstrated that up to 90 percent of rods might be lost before the patient notices any visual abnormalities.
What Is Retinitis Pigmentosa?
Retinitis pigmentosa (RP) is a diverse collection of inherited conditions that cause the photoreceptor cells in the retina to progressively deteriorate, beginning with the rods. As a result, vision gradually deteriorates over time. It is the most prevalent form of hereditary retinal dystrophy and places a heavy cost on individuals as well as the general public. Over 1.5 million individuals are affected globally, making it one of the main causes of vision impairment and blindness in persons under 60. Nyctalopia and a progressive loss of peripheral vision that eventually results in blindness are common symptoms of RP despite the varied phenotypes of the illnesses.
What Is the Gene Therapy for Retinitis Pigmentosa?
Particularly in the treatment of hereditary retinal illnesses, gene therapy has seen a significant amount of development in recent years. Based on the disease's inheritance pattern, there are primarily two gene therapy methods that can be used for RP. The goal is to use a gene complementation strategy in recessive RP, which manifests a loss of function of the target protein. Gene therapy methods for dominant RP include gene suppression with or without gene complementation.
Numerous gene therapy techniques have been developed employing viral or non-viral vectors to reach the therapeutic objective of RP treatment.
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Viral Vectors: Numerous viral vectors have made it to clinical investigations and have been used in gene therapy for the treatment of RP. Adenoviruses (Ad), Adeno-associated viruses (AAV), and Lentiviruses (LV) are the three primary categories of viral vector techniques. AAV has received attention recently because of its intriguing possibilities. They were identified as non-enveloped icosahedral viruses with a modest size (25 nm) when they were first described in 1996. AAVs are preferred in gene therapy procedures for the treatment of Inherited retinopathies (IR) because of their favorable characteristics; their tiny size allows for the effective targeting of retinal layers. AAV also has minimal immunogenicity, which enables safe second-dose delivery in the subretinal area as well as extended-expression of the target gene following single-dose therapy. Due to their high seroprevalence, Ad-based vectors cause a pre-immunity, which jeopardizes Ad-based gene treatments. Contrarily, despite their potential presence, AAVs are not harmful and have not yet been connected to human illnesses.
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CRISPR-Cas Gene Editing System: A cutting-edge technology commonly employed in gene expression and suppression techniques is the CRISPR-Cas9 gene editing system. Its use has demonstrated the ability to effectively quiet dominant mutations in retinal disorders through the NHEJ (Non-homologous end joining) pathway. Although improved success rates for gene editing have been observed in vitro, the CRISPR-Cas9 system's lower performance rates provide a significant obstacle to its clinical implementation. The design of the guide RNA (sgRNA), the kind of cell target, the delivery vehicle (viral or non-viral vectors), and host-related parameters are all crucial for the effectiveness of gene editing. Nevertheless, even a modest amount of gene change can result in an improvement in phenotype, suggesting that CRISPR-Cas9 gene editing may be important for hereditary retinal illnesses.
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RNA Replacement: Depleting endogenous mutant RNAs is the procedure used in RNA replacement therapy. The main players in the control of gene expression are noncoding RNAs (ncRNA). In ncRNA, three primary regulatory components fall under the categories of micro-RNA (miRNA), small interfering RNA (siRNA), and short hairpin RNA (shRNA). By attaching to a target messenger RNA's (mRNA) binding sites, a miRNA controls post-transcriptional changes. This further causes translational suppression and mRNA instability. The control of protein-coding gene expression involves the RNA interference (RNAi) mechanism. A kind of miRNA called a mirtron is an RNAi effector that may be exploited in gene therapy. Further discussion is given on their use in the treatment of RP. Similar to miRNA, siRNA is a double-stranded RNA. However, unlike miRNA, which can discriminate between single nucleotide differences, siRNA's binding ability is very specific. While siRNA regulates RNA effector molecules, shRNA operates on DNA delivery and shares structural similarities with miRNA transcripts. Antisense oligonucleotides (ASO), a kind of synthetic single-stranded RNA, have also been demonstrated to have therapeutic benefits in hereditary retinal disorders.
What Are Other Treatment Options?
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Correcting RPE65 Gene Mutations:
Only individuals with mutations in both copies of the RPE65 gene are eligible for the gene therapy Luxturna. This mutation impairs the retina's ability to react to light. A healthy copy of the RPE65 gene is directly delivered to the retina by a single injection of Luxturna. The retina's capacity to react to light is restored as a result.
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X-Linked Retinitis Pigmentosa Gene Therapy:
Three firms, Meira GTX, Applied Genetic Technologies, and BioGen, are working on experimental gene treatments that may help people with the aggressive type of X-linked retinitis pigmentosa. Men are more frequently affected by this disorder, which is brought on by an RPGR gene mutation.
A technique termed vitrectomy and an injection into the eye that distributes healthy copies of the RPGR gene to the macula, a region of the retina, is used in all three therapies. Clinical study participants who had treatment in one eye reported improvements in their field of vision, light sensitivity, and capacity for navigating in low light. Another kind of gene therapy without a vitrectomy is being tested by a business called 4D Molecular Therapeutics.
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Repairing the USH2A Gene's Flaws:
A gene treatment being developed may prevent vision loss in persons with Usher syndrome and retinitis pigmentosa caused by a mutation in the USH2A gene. Patients who have this mutation are unable to produce the USH2A protein, which is necessary for eyesight. The treatment, known as QR-421a, is injected into the retina and enables cells to make a more beneficial USH2A protein. So far, both visual acuity and field of vision have improved in individuals with advanced and early-moderate illness.
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Repairing the RHO Gene's Flaws:
A therapy for persons with retinitis pigmentosa caused by a mutation in the RHO gene is being tested in different research. This also goes by the name RP4. A defective form of the rhodopsin protein, which typically transforms light into an electrical signal, is produced by people who have this mutation. Over time, the retina is poisoned by the defective protein. The brand-new medication, QR-1123, works by stopping the production of the defective protein and is administered through ocular injection. This enables the protein's regular form to once more control the retina. A phase 1-2 clinical trial is now investigating this treatment.
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Treating Type 10 Leber Congenital Amaurosis:
Infants who have Leber congenital amaurosis suffer from retinitis pigmentosa, a kind of disease. The retina's light-sensing cells are destroyed by this illness. A CEP290 gene deficiency that results in type 10 illness and, frequently, legal blindness causes gradual visual loss.
There are two potential medicines under research for this therapy. CRISPR is a gene-editing technique that scientists have created to attempt to fix the genetic flaw. During an eye injection, the retina receives the therapy. The tool is intended to assist the retina in producing a protein that both delays cell death and revives certain already deceased cells. This could aid in patients' visual recovery. These therapies may be able to prevent people from suffering from retinitis pigmentosa's crippling vision loss.
Conclusion
In recent years, the science of gene therapy has advanced significantly in medicine, including ophthalmology. The greatest gene therapy options are those that are straightforward, do not require a lot of repetition, have the best effectiveness outcomes, have the fewest safety issues, and place the least financial strain on patients and healthcare systems. To treat a once-incurable, blinding RP, doctors should stay current on both the pathogenesis of the illness and recent advances in gene therapy.
